2-Substituted-5-oxo-5H-dibenzo [a,d] -cycloheptene esters

ABSTRACT

2-Substituted-5-oxo-5H-dibenzo [a,d] cycloheptenes represented by the following formula: ##STR1## where one of R 2  and R 3  is hydrogen, and the other is hydrogen, methyl, or ethyl, or together R 2  and R 3  are methylene; the dotted line represents an optional, additional bond between the carbon atoms at the 10- and 11-positions; and the pharmaceutically acceptable esters and ethers thereof. The compounds have anti-inflammatory, analgesic, and antipyretic activities and, accordingly, are useful in the treatment of inflammation, pain and pyrexia.

CROSS-REFERENCE TO PARENT APPLICATION

This application is a divisional application of application Ser. No.581,501, filed May 30, 1975 now U.S. Pat. No. 3,966,820 which, in turn,is a continuation-in-part of application Ser. No. 486,038, filed July 5,1974, now abandoned.

FIELD OF THE INVENTION

This invention relates to novel chemical compounds. More particularly,this invention relates to novel pharmaceutically active5-oxo-5H-dibenzo[a,d]cycloheptene derivatives substituted at the2-position with an ethanol moiety or an α-substituted ethanol moiety,and the pharmaceutically acceptable esters and ethers thereof.

SUMMARY OF THE INVENTION

The novel 5-oxo-5H-dibenzo[a,d]cycloheptene-2-substituted derivatives ofthe present invention can be represented by the following formula:##STR2## where one of R² and R³ is hydrogen and the other is hydrogen,methyl, or ethyl, or together R² and R³ methylene; the dotted linerepresents an optional, additional bond between the carbon atoms at the10- and 11-positions; and the pharmaceutically acceptable esters andethers thereof.

As used in this specification and claims, the term "pharmaceuticallyacceptable ester" denotes those hydrolyzable ester groups conventionallyemployed in this art, preferably those derived from hydrocarboncarboxylic acids or their salts. The term "hydrocarbon carboxylic acid"refers to both substituted and unsubstituted hydrocarbon carboxylicacids. These acids can be completely saturated or possess varyingdegrees of unsaturation (including aromatic), can be of straight chain,branched chain, or cyclic structure and preferably contain from 1 to 12carbon atoms. Typical conventional hydrolyzable esters, expressed as theradical, thus included within the scope of the term as defined above areacetate, propionate, 2-methylpropionate, butyrate, valerate, caproate,enanthate, caprylate, benzoate, 2acetoxybenzoate, salicylate,phenylacetate, diethylacetate, trimethylacetate, t-butylacetate,cyclohexylacetate, cyclopentylpropionate, adamantoate,bicyclo[2.2.2]octyl carboxylate, hemisuccinate, hemiadipate,hemi-β,β-dimethylglutarate, and the like.

As used in this specification and claims, the term "pharmaceuticallyacceptable ether" refers to those ether groups conventionally employedin this art, preferably those derived from straight chain, branchedchain, aromatic hydrocarbons and oxo heterocyclic hydrocarbons. The term"hydrocarbons" refers to both saturated and unsaturated hydrocarbons,which can be optionally substituted with groups such as hydroxy, alkoxy,halo, alkylthio, and the like. Preferably, the hydrocarbons contain from1 to 12 carbon atoms. Typical ethers thus included within the scope ofthis definition include, for example, alkoxy, such as methoxy, ethoxy,propoxy, and the like; difluoromethoxy; alkoxymethoxy, such asmethoxymethoxy, ethoxymethoxy, and the like; tetrahydrofuran-2'-yloxy;tetrahydropyran-2'-yloxy; and 4'-alkoxytetrahydropyran-4'-yloxy, such as4'-methoxytetrahydropyran-4'-yloxy; and the like.

When one of R² and R³ is hydrogen and the other is methyl or ethyl, thecompounds of Formula I exist as pairs of enantiomorphs. Eachenantiomorph or optical isomer and mixtures thereof are included withinthe present invention. The compounds of Formula I which exist as pairsof enantiomorphs can be administered as racemic mixtures or they can beadministered as resolved enantiomorphs. In some instances, oneenantiomorph exhibits greater anti-inflammatory, analgesic and/orantipyretic activity than the other corresponding enantiomorph.

The optical isomers can be resolved by conventional means, such asselective biological degradation; or by preparing the correspondingcarboxylic acids, followed by preparing the diastereoisomer salts oresters thereof with an optically active amine, such as (l)-amphetamine,or an optically active alcohol such as -(d)-α-phenylethanol, separatingthe diastereoisomer salts or esters by fractional crystallization,cleaving the salts or esters to form the optically resolved isomer(s) ofthe carboxylic acid, and then converting the acid to the correspondingalcohol to thereby afford the optically resolved isomer(s) of thecompound of Formula I.

Preferably, the resolved compounds of Formula I can be prepared from thecorresponding resolved starting compounds used to prepare the compoundsof Formula I. The resolved compounds of Formula I and the respectiveresolved starting compound will not necessarily have the same opticalrotation, although they will have the same absolute configuration. Forexample, (1)-2-(5-oxo-5H-dibenzo[a,d]cyclohepten-2-yl)propan-1-ol isprepared from (d) 2-(5-oxo-5H-dibenzo[a,d]cyclohepten-2-yl)propionicacid; etc.

The compounds of Formula I exhibit anti-inflammatory, analgesic andanti-pyretic activities. Accordingly, the compositions of this inventionare useful in the treatment and elimination of inflammation such asinflammatory conditions of the muscular skeletal system, skeletal jointsand the other tissues, for example, the treatment of inflammatoryconditions such as rheumatism, concussion, laceration, arthritis, bonefractures, post-traumatic conditions, and gout. In those cases in whichthe above conditions include pain and pyrexia coupled with inflammation,the instant compounds are useful for the relief of these conditions aswell as the inflammation.

Administration of the active compound of Formula I in an appropriatepharmaceutical composition can be via any of the accepted modes ofadministration of agents for the treatment of inflammation, pain, orpyrexia. Thus, administration can be, for example, orally, parenterally,per os, or topically, in the form of solid, semi-solid or liquid dosageforms, such as, for example, tablets, suppositories, pills, capsules,powders, liquid solutions, suspensions, creams, lotions, ointments, orthe like, preferably in unit dosage forms suitable for simpleadministration of precise dosages. The compositions of this inventionwill include a conventional pharmaceutical carrier or excipient and anactive compound of Formula I, and, in addition, may include othermedicinal agents, pharmaceutical agents, carriers, adjuvants, etc.

The preferred manner of administration is oral using a convenient dailydosage regimen which can be adjusted according to the degree ofaffliction. Generally, a daily dose of from 0.1 mg. to 30 mg. of theactive compound of Formula I per kilogram of body weight is used. Mostconditions respond to treatment comprising a dosage level of the orderof 1 mg. to 10 mg. per kilogram of body weight per day. For such oraladministration, a pharmaceutically acceptable non-toxic composition isformed by the incorporation of any of the normally employed excipients,such as, for example, pharmaceutical grades of mannitol, lactose,starch, magnesium stearate, sodium saccharin, talcum, cellulose,glucose, sucrose, magnesium carbonate, and the like. Such compositionstake the form of solutions, suspensions, tablets, pills, capsules,powders, sustained release formulations and the like.

The active compound of Formula I may be formulated into a suppositoryusing, for example, polyalkylene glycols, for example, polypropyleneglycol, as the carrier Liquid pharmaceutically administerablecompositions can, for example, be prepared by dissolving, dispersing,etc. an active compound of Formula I and optional pharmaceuticaladjuvants in a carrier, such as, for example, water, saline, aqueousdextrose, glycerol, ethanol, and the like, to thereby form a solution orsuspension. If desired, the pharmaceutical composition to beadministered may also contain minor amounts of non-toxic auxiliarysubstances such as wetting or emulsifying agents, pH buffering agentsand the like, such as for example, sodium acetate, sorbitan monolaurate,triethanolamine oleate, etc.

Actual methods of preparing such dosage forms are known, or will beapparent, to those skilled in this art; for example, see Remington'sPharmaceutical Sciences, Mack Publishing Company, Easton, Pennsylvania,14th. Edition, 1970. The composition to be administered will, in anyevent, contain a quantity of the active compound(s) in apharmaceutically effective amount for relief of the particular conditionbeing treated in accordance with the teachings of this invention.

The compounds of this invention are also uterine smooth muscle relaxantsand thus are useful as agents for maintaining the pregnancy of pregnantmammals, for the benefit of the mother and/or the fetus, untiltermination of the pregnancy is considered, from a medical point ofview, to be favorable, or more favorable, for the mother and/or thefetus. It should be understood, however, that in certain instances, forexample where parturition has already begun (i.e., the mother isexperiencing uterine contractions, especially near full term), thatadministration of the compounds of this invention may not maintain thepregnant state for an indefinite period of time. Rather, in suchinstances, the pregnancy will, most probably, be slightly "prolonged," afactor which may be advantageous to either the mother and/or the fetus.

The compounds of this invention are also used as agents for delaying theonset of, or for postponing, parturition. As used in this application,the phrase "to delay the onset of parturition" is intended to cover thatdelay in parturition caused by the administration of an active compoundat any time before uterine muscle contractions have begun. Thus, it isintended that the aforementioned phrase cover abortion prevention earlyin pregnancy (i.e., before the fetus is "viable") as well as delayingpremature parturition, a term which sometimes is used with reference tothat premature labor experienced later in the pregnancy when the fetusis considered to be "viable". In either case, the agents areadministered as prophylatic agents in that such administration tends toprevent the onset of parturition. This administration is particularlyuseful in the treatment of women having a history of spontaneousabortion, miscarriage or premature delivery (i.e., delivery prior tofull term). Such administration is also useful where there are clinicalindications that the pregnancy might be terminated prior to that timeconsidered favorable to the mother and/or fetus.

As used in this application, the phrase "postponing parturition" isintended to cover that delay in parturition caused by the administrationof an active compound after uterine muscle contractions have begun. Thecondition of the patient, including the time within the gestation periodwhen the contractions have begun, the severity of the contractions andhow long the contractions have taken place will affect the resultsachieved. For example, the effect can be to reduce the intensity and/orthe duration of the contractions (the actual act of parturition being"prolonged"), or to stop the contractions altogether. In either case,the effect will be to prolong the gestation period although, dependingupon the condition of the patient as described above, the effect mayeither be slight or, under appropriate circumstances, somewhat greater.Such administration may be to prevent spontaneous abortion, to cause thedelivery to be more easily accomplished and/or less painful to themother, or to occur at a more appropriate time and/or place.

With respect to animals, this treatment can also be utilized tosynchronize the deliveries from a group of pregnant animals to happen ator about the same time, or to happen at or about a desired time and/orplace, when the births can be handled with greater facility.

In all cases, administration should be consistent with best and/oraccepted medical (or veterinary) practices so as to maximize thebenefits to the mother and the fetus. For example, administration shouldnot be continued so long past full term that the fetus dies in utero.

In the practice of this aspect of the present invention, an effectiveamount of a compound of this invention or a pharmaceutical compositioncontaining such a compound is administered to the pregnant mammal viaany of the usual and acceptable methods known in the art. The compoundcan be administered either singly or in combination with anothercompound or compounds, as defined above, or other pharmaceutical agents,carriers, adjuvants, etc. Such compound(s) or compositions can beadministered orally or parenterally in the doses and in the forms(including oral, vaginal or uterine tablets or suppositories, etc.) asset forth above regarding anti-inflammatory, etc. activities.Administrations can be a single dose or up to 3 or 4 smaller dosesregularly given throughout the day. The actual amount of active compoundadministered will, of course, depend on its relative activity for thisparticular utility.

The compounds of Formula I above are prepared by treating thecorresponding alkanoic acid compound, for example(5-oxo-5H-dibenzo[a,d]cyclohepten-2-yl)acetic acid or2(5-oxo-5H-dibenzo[a,d]cyclohepten-2-yl)propionic acid, or thecorresponding 10,11-dihydro compounds, with lithium aluminum hydride atabout 0° C. to the boiling point of the reaction medium, preferablyabout room temperature, for about one-fourth hour to about 4 hours,generally about 1 hour or so, in an inert organic ether, such as diethylether, dipropyl ether, diisopropyl ether, dibutyl ether, and the like.The ethereal solution, after addition of water, separation andfiltration, is treated with manganese dioxide at about 0° C. to aboutthe boiling point of the reaction medium, also preferably about roomtemperature, for about 2 to about 96 hours, generally about 8 hours orso. The product compound is then isolated and purified according tostandard procedures known to those skilled in this art.

The starting alkanoic acid compounds referred to above can be preparedby conducting an Arndt-Eistert reaction upon5-oxo-5H-dibenzo[a,d]cycloheptene-2-carboxylic acid to afford(5-oxo-5H-dibenzo[a,d]cyclohepten-2-yl)-acetic acid or2(5-oxo-5H-dibenzo[a,d]cyclohepten-2-yl)-propionic acid. In similarmanner starting with5-oxo-10,11-dihydro-5H-dibenzo[a,d]cycloheptene-2-carboxylic acid, thecorresponding 5-oxo-5H-dibenzo[a,d]cycloheptane-2-alkanoic acids can beprepared.

5-Oxo-5H-dibenzo[a,d]cycloheptene-2-carboxylic acid is prepared byesterifying 2-methylterephthalic acid with methanol, in the presence ofacid catalyst, to afford the corresponding dimethyl ester which, inturn, is reacted with N-bromosuccinimide to afford2-bromomethylterephthalic acid dimethyl ester. This diester is reactedwith triphenylphosphine to afford 2,5-bis(carbomethoxy)benzyltriphenylphosphonium bromide which is treated with benzaldehyde and anon-nucleophilic base, such as diazabicylononene, to afford, afteralkaline hydrolysis, cis and trans stilbene 2,5-dicarboxylic acid.Hydrogenation of this latter compound with hydrogen over a 5% palladiumon carbon catalyst affords 2-(2-phenethyl)terephthalic acid. Treatmentwith polyphosphoric acid yields5-oxo-5H-dibenzo[a,d]cycloheptane-2-carboxylic acid which can berecystallized from aqueous dimethylformamide.5-oxo-5H-dibenzo[a,d]cycloheptene-2-carboxylic acid is prepared bysuccessively treating 5-oxo-5H-dibenzo[a,d]cycloheptane-2-carboxylicacid with diazomethane, N-bromosuccinimide, anddimethylformamide/diazabicyclononene, followed by base hydrolysis andacidification.

In the Arndt-Eistert reaction, the carboxylic chain of the starting2-carboxylic acid compound is elongated by treating the 2-carboxycompound with thionyl chloride to obtain the acid chloride. This acidchloride is reacted with the diazomethane to form a diazoketone which isrearragned by the action of a silver salt in the presence of an alcohol,for example, methanol or ethanol. The resultant alkyl ester of the2-acetic acid compound can be hydrolyzed to afford the free 2-aceticacid. Or, the resultant compound can be treated with an alkali metalhydride, amide, or dialkyl amide, such as sodium hydride, lithiumisopropylcyclohexyl amide or sodium dimethyl amide, followed bytreatment with an alkyl halide, such as methyl iodide or ethyl iodide,to α-alkylate the 2-acetic acid ester compound, thereby forming thecorresponding 2-propionic acid ester or the 2-butyric acid ester, whichalso can be hydrolyzed to form the corresponding 2-propionic acid or2-butyric acid compounds, respectively. Optionally, the 2-propionic acidcompound can be prepared, without the need for α-methylation, byreacting 2-chloroformyl-5-oxo-5H-dibenzo[a,d]cycloheptene with etherealdiazoethane, followed by treatment with N,N-dimethylaniline and benzylalcohol, base hydrolysis and acidification. The Arndt-Eistert reactionis a well-known series of steps, the particulars of which can bedetermined by reference to the Examples below or to the articles thereonin the published literature.

The α,α-methylene group is introduced by treating the 2-carboxy compoundwith thionyl chloride, then ethereal diazomethane to afford thecorresponding 2-diazoacetyl compound, which is then treated with aqueousacid and copper powder in a water-miscible, organic solvent at elevatedtemperatures to afford the corresponding 2-hydroxyacetal compound. Thelatter compound is reacted, at elevated temperatures, with methyleneiodide in the presence of a zinc-copper couple to afford thecorresponding α,α-methylene-ethan-1-ol compound.

The compounds of Formula I can be esterified or etherified viaconventional techniques. For example, the compounds can be esterified bytreatment with an acid anhydride, such as acetic anhydride, valericanhydride, caproic anhydride, and the like, in pyridine; or by treatmentwith an acid chloride, such as acetyl chloride, adamantoyl chloride, andthe like, in acetonitrile and triethylamine; or by treatment with acarboxylic acid in the presence of an acid catalyst, such asp-toluenesulfonic acid, and the like. The compounds of Formula I can beetherified by treatment with an alkali metal hydride, such as sodiumhydride, and an organic halide, such as cyclopentyl chloride,2-chlorotetrahydropyran, 2-chlorotetrahydrofuran, and the like; or bytreatment with dihydrofuran, dihydropyran, 4-methoxydihydropyran, andthe like, in the presence of an acid catalyst.

In each of the process steps, described herein above and below, unlessotherwise indicated, the respective intermediate products are preferablyseparated from the reaction mixture and purified prior to their use asstarting materials for the next step in the process. Such separation andpurification can be effected by any suitable procedure For example,typical separation procedures include filtration, extract ion,evaporation, and typical purification procedures includecrystallization, and both thin-layer and column chromatography. Optimumseparation and isolation procedures can be obtained for any given stepby routine experimentation as will be apparent to those skilled in thisart.

Particular compounds falling within the scope of the present inventioncan be prepared by selecting an appropriate starting material, forexample, from those referred to above, and then selecting particularreaction step or steps, as for example described above, to give thecompound desired. In view of this disclosure, the preparation ofparticular compounds, including compounds falling within the presentinvention but not specifically described in this specification, will beapparent to those skilled in this art.

In this specification, the2-substituted-10,11-dihydro-5-oxo-5H-dibenzo[a,d]cycloheptenes of thisinvention are also referred to as the corresponding2-substituted-5-oxo-5H-dibenzo[a,d]cycloheptanes, it being understoodthat both designations refer to the compounds of Formula I where thereis a single bond between the carbon atoms at the 10- and 11-positions.

Exemplary of the compounds of the present invention, as represented bythe structural formula above, are the following illustrated compounds:

2-(5-oxo-5H-dibenzo[a,d]cyclohepten-2-yl)ethan-1-ol;

2-(5-oxo-5H-dibenzo[a,d]cycloheptan-2-yl)propan-1-ol;

2-(5-oxo-5H-dibenzo[a,d]cyclohepten-2-yl)butan-1-ol;

2-(5-oxo-5H-dibenzo[a,d]cyclohepten-2-yl)prop-1-en-3-ol;

2-(5-oxo-5H-dibenzo[a,d]cyclohepten-2-yl)eth-1-yl acetate;

2-(5-oxo-5H-dibenzo[a,d]cyclohepten-2-yl)prop-1-yl acetate;

2-(5-oxo-5H-dibenzo[a,d]cyclohepten-2-yl)but-1yl acetate;

2-(5-oxo-5H-dibenzo[a,d]cyclohepten-2-yl)prop-1-en-3-yl acetate;

2-(5-oxo-5H-dibenzo[a,d]cyclohepten-2-yl)eth-1-yl propionate;

2-(5-oxo-5H-dibenzo[a,d]cyclohepten-2-yl)prop-1-yl propionate;

2-(5-oxo-5H-dibenzo[a,d]cyclohepten-2-yl)but-1-yl propionate;

2-(5-oxo-5H-dibenzo[a,d]cyclohepten-2-yl)prop-1en-3-yl propionate;

2-(5-oxo-5H-dibenzo[a,d]cyclohepten-2-yl)prop-1-yl n-butyrate;

2-(5-oxo-5H-dibenzo[a,d]cyclohepten-2-yl)prop-1-yl 3'-methylbutyrate;

2-(5-oxo-5H-dibenzo[a,d]cyclohepten-2yl)prop-1-yl n-pentanoate;

2-(5-oxo-5H-dibenzo[a,d]cyclohepten-2-yl)prop-1-yl n-hexanoate;

2-(5-oxo-5H-dibenzo[a,d]cycloheptan-2-yl)ethan-1-ol;

2-(5-oxo-5H-dibenzo[a,d]cycloheptan-2-yl)propan-1-ol;

2-(5-oxo-5H-dibenzo[a,d]cycloheptan-2-yl)butan-1-ol;

2-(5-oxo-5H-dibenzo[a,d]cycloheptan-2-yl)prop-1en-3-ol;

2-(5-oxo-5H-dibenzo[a,d]cycloheptan-2-yl)eth-1-yl acetate;

2-(5-oxo-5H-dibenzo[a,d]cycloheptan-2yl)prop-1-yl acetate;

2-(5-oxo-5H-dibenzo[a,d]cycloheptan-2-yl)but-1-yl acetate;

2-(5-oxo-5H-dibenzo[a,d]cycloheptan-2-yl)prop-1en-3-yl acetate;

2-(5-oxo-5H-dibenzo[a,d]cycloheptan-2yl)eth-1-yl propionate;

2-(5-oxo-5H-dibenzo[a,d]cycloheptan-2-yl)prop-1-yl propionate;

2-(5-oxo-5H-dibenzo[a,d]cycloheptan-2-yl)but-1-yl propionate;

2-(5-oxo-5H-dibenzo[a,d]cycloheptan-2-yl)prop-1en-3-yl propionate;

2-(5-oxo-5H-dibenzo[a,d]cycloheptan-2-yl)prop-1-yl butyrate;

2-(5-oxo-5H-dibenzo[a,d]cycloheptan-2-yl)prop-1-yl 3'-methylbutyrate;

2-(5-oxo-5H-dibenzo[a,d]cycloheptan-2-yl)prop-1-yl n-pentanoate;

2-(5-oxo-5H-dibenzo[a,d]cycloheptan-2-yl)prop-1-yl n-hexanoate;

1-ethoxy(or 2-tetrahydropropanylether)-2-(5-oxo-5H-dibenzo[a,d]cyclohepten-2-yl)propane;

and the corresponding l and d isomers of those compounds which have anassymetric carbon atom.

DESCRIPTION OF SPECIFIC EMBODIMENTS

The following specific description is given to enable those skilled inthis art to more clearly understand and practice the present invention.It should not be considered as a limitation upon the scope of theinvention but merely as being illustrative and representative thereof.

Preparation 1

148 G. of 2-methylterephthalic acid is refluxed for 24 hrs. in 750 ml.of dry methanol containing 30 ml. of sulphuric acid. The solution iscooled, poured into water and extracted with ether. The extract iswashed, dried and evaporated to give dimethyl-2-methylterephthalate.

88 G. of dimethyl-2-methylterephthalate in 1000 ml. of carbontetrachloride containing 89 g. (1 mole) of N-bromosuccinimide isrefluxed for 3 hours using a heat lamp. The solution is cooled, filteredand evaporated to dryness to give dimethyl -2-bromomethylterephthalate

25.7 G. of dimethyl-2-bromomethylterephthalate is refluxed in 250 ml. ofacetonitrile containing 26.2 g. (1 mole) of triphenylphosphine for 4hrs. The solution is cooled and diluted with 1250 ml. of ether therebyprecipitating 2,5-bis(carbomethoxy)-benzyltriphenylphopshonium bromidewhich is filtered off and dried under vacuum.

51.9 G. of 2,5-bis(carbomethoxy)-benzyltriphenylphosphonium bromide and10.6 g. of benzaldehyde are stirred in 300 ml. of acetonitrile and 12.4g. of diazabicyclononene is added. The mixture is heated briefly toreflux, then cooled and evaporated to an oil. The oil is dissolved inethyl acetate, and the solution washed with dilute hydrochloric acid,dried and evaporated. The residue is refluxed for 12 hrs. in a solutionof 20 g. of potassium hydroxide in 300 ml. of water and 50 ml. ofmethanol. The solution is cooled and extracted with chloroform. Theaqueous solution is acidified with dilute hydrochloric acid and theprecipitated cis and trans stilbene-2,5-dicarboxylic acid is filteredoff and dried.

23.6 G. of cis and trans-stilbene-2,5-dicarboxylic acid is dissolved in100 ml. of dimethylformamide containing 500 mg. of 5% palladium oncarbon and hydrogenated for 2 hrs. The solution is filtered andevaporated to dryness to give a crude product which uponrecrystallization from aqueous ethanol yields2-(2-phenethyl)terephthalic acid.

23.8 G. of 2-(2-phenethyl)terephthalic acid is dissolved in 200 ml. ofsulpholane at 130° C. and 150 ml. of polyphosphonic acid is added withstirring. The mixture is stirred at 130° C. for 4 hrs., then poured into1000 ml. of water. The product is filtered off and recrystallizationfrom aqueous dimethylformamide to yield5-oxo-5H-dibenzo[a,d]-cycloheptane-2-carboxylic acid.

Preparation 2

5.0 G. of 5-oxo-5H-dibenzo[a,d]cycloheptane-2-carboxylic acid (asprepared in Preparation 1 above) is suspended in 50 ml. of dioxane,added to excess ethereal diazomethane, and stirred until dissolution iscomplete. The solution is then evaporated to dryness to yield2-carbomethoxy-5-oxo-5H-dibenzo[a,d]cycloheptane.

4.68 G. of 2-carbomethoxy-5-oxo-5H-dibenzo[a,d]cycloheptane is refluxedin 100 ml. of carbon tetrachloride containing 3.56 g. (1 eg.) ofN-bromosuccinimide while being irradiated with a 100 watt incandescentlamp. After 2 hrs. the solution is cooled, filtered and evaporated todryness. The residue is dissolved in 30 ml. of dimethylformamide and2.48 g. (1 eg.) of diazabicyclononene is added. The mixture is heatedbriefly to 60° C., and water and ethyl acetate are added. The organiclayer is washed with dilute hydrochloric acid and water, then dried andevaporated to give 2-carbomethoxy-5-oxo-5H-dibenzo[a,d]cycloheptene.Hydrolysis in eight to one aqueous methanol, 5% potassium hydroxide,followed by acidification with dilute hydrochloric acid yields5-oxo-5H-dibenzo[a,d]cycloheptene-2-carboxylic acid.

Preparation 3

22 G. of 5-oxo-5H-dibenzo[a,d]cycloheptane-2-carboxylic acid is stirredin 200 ml. of chloroform, 50 ml. of thionyl chloride and 1 ml. ofdimethylformamide for 8 hrs. The mixture is evaporated to dryness andthe residue recrystallized from acetonitrile to yield2-chloroformyl-5-oxo-5H-dibenzo[a,d]cycloheptane. This is dissolved in200 ml. of chloroform and added to a 3-fold excess of etherealdiazomethane at 0° C. The mixture is left at 0° C. for 12 hrs. thenevaporated to dryness. The residue is recrystallized from acetonitrileto yield 2-diazoacetyl-5-oxo-5H-dibenzo[a,d]cycloheptane. Thediazoketone is heated to reflux in 250 ml. of ethanol and a saturatedtriethylamine solution of 2 g. of silver benzoate is added slowly untilgas evolution ceases. The solution is cooled, filtered and evaporated toyield ethyl (5-oxo-5H-dibenzo[a,d]cycloheptan-2-yl)acetate. This esteris refluxed in 5% aqueous potassium hydroxide for 12 hrs. The solutionis cooled, acidified with dilute hydrochloric acid and extracted withether. The ether extract is dried and evaporated to yield(5-oxo-5H-dibenzo[a,d]cycloheptan-2-yl)acetic acid which can berecrystallized from acetone-hexane.

Preparation 4

Lithium isopropylcyclohexylamide is prepared by adding 10 mls. of 1.0molar n-butyl lithium to a solution of 1.41 g. ofisopropylcyclohexylamine in 100 ml. of dry tetrahydrofuran. To thissolution, cooled to -80° C., there is added a solution of 2.82 g. ofethyl (5-oxo-5H-dibenzo[a,d]cycloheptan-2-yl)acetate (as prepared inPreparation 3 above) in 10 ml. of tetrahydrofuran. The mixture is leftfor 5 minutes, then 1.42 g. of methyl iodide is added. The reaction isallowed to attain room temperature, then water and ether are added. Theethereal layer is washed with dilute hydrochloric acid and water, driedand evaporated to yield ethyl2-(5-oxo-5H-dibenzo[a,d]cycloheptan-2-yl)propionate. This ethyl ester isrefluxed for 12 hrs. in 5% aqueous potassium hydroxide, followed byacidification with dilute hydrochloric acid and ether extraction toafford 2-(5-oxo-5H-dibenzo[a,d]cycloheptan-2-yl)propionic acid.

In a similar manner substituting ethyl iodide for the methyl iodideabove, there is prepared2-(5-oxo-5H-dibenzo[a,d]cycloheptan-2-yl)butyric acid.

Preparation 5

In similar manner to the procedure of Preparations 3 and 4 substituting5-oxo-5H-dibenzo[a,d]cycloheptene-2-carboxylic acid for the5-oxo-5H-dibenzo[a,d]cycloheptane-2-carboxylic acid of Preparation 3,there is prepared ethyl (5-oxo-5H-dibenzo[a,d]cyclohepten-2-yl)acetate,(5-oxo-5H-dibenzo[a,d]cyclohepten-2-yl)acetic acid,2-(5-oxo-5H-dibenzo[a,d]cyclohepten-2-yl)propionic acid, and2-(5-oxo-5H-dibenzo[a,d]cyclohepten-2-yl) acid.

EXAMPLE I

0.5 G. of lithium aluminum hydride is added to a solution of 2.78 g. of2-(5-oxo-5H-dibenzo[a,d]cyclohepten-2-yl)propionic acid in 200 ml. ofanhydrous ether. The mixture is stirred for 2 hours and then excesshydride is destroyed by sequential addition of ethyl acetate, methanoland water. The ethereal solution is separated and filtered and to it isadded 15 g. of activated manganese dioxide. The mixture is stirred for 8hours, then filtered through 10 g. of silica gel and the eluateevaporated to afford2-(5-oxo-5H-dibenzo[a,d]cyclohepten-2-yl)propan-1-ol (m.p. 63°-66° C.).

In similar manner substituting:

(5-oxo-5H-dibenzo[a,d]cyclohepten-2-yl)acetic acid,

2-(5-oxo-5H-dibenzo[a,d]cyclohepten-2-yl)butyric acid,

(5-oxo-5H-dibenzo[a,d]cycloheptan-2-yl)acetic acid,

2-(5-oxo-5H-dibenzo[a,d]cycloheptan-2-yl)propionic acid, or

2-(5-oxo-5H-dibenzo[a,d]cycloheptan-2-yl)butyric acid, for the2-(5-oxo-5H-dibenzo[a,d]cyclohepten-2-yl)propionic acid, the followingare prepared:

2-(5-oxo-5H-dibenzo[a,d]cyclohepten-2-yl)ethan-1-ol,

2-(5-oxo-5H-dibenzo[a,d]cyclohepten-2-yl)butan-1-ol,

2-(5-oxo-5H-dibenzo[a,d]cycloheptan-2-yl)ethan-1-ol,

2-(5-oxo-5H-dibenzo[a,d]cycloheptan-2-yl)propan-1-ol,

[a gum; nmr spectrum in deuterochloroform relative to tetramethylsilane:1.25 (doublet, CH₃), 1.60 (singlet, OH), 3.16 (singlet, 10H, 11H) and3.70 ppm (doublet, CH₂ OH)], and

2-(5-oxo-5H-dibenzo[a,d]cycloheptan-2-yl)butan-1-ol, respectively.

EXAMPLE II

A solution of 2.50 g. of 2-carboxy-5-oxo-5H-dibenzo[a,d]cycloheptene in50 ml. of chloroform, 10 ml. of thionyl chloride and 0.3 ml. ofdimethylformamide is stirred for 8 hours, then evaporated to dryness andthe residue recrystallized from acetonitrile to yield2-chloroformyl-5-oxo-5H-dibenzo[a,d]cycloheptene. This is dissolved in50 ml. of chloroform and added to a 3-fold excess of etherealdiazomethane at 0° C. After 12 hours the solution is evaporated todryness and the residue recrystallized from acetonitrile to yield2-diazoacetyl-5-oxo-5H-dibenzo[a,d]cycloheptene. A solution of 1.37 g.of the latter compound in 50 ml. of tetrahydrofuran is added to 10 ml.of 0.1 N sulfuric acid containing 0.5 g. of copper powder. The mixtureis refluxed for 3 hours and then cooled, filtered and poured into water.The solution is extracted with ethyl acetate and the extract washed,dried and evaporated to yield2-hydroxyacetyl-5-oxo-5H-dibenzo[a,d]cycloheptene which isrecrystallized from chloroform/hexane. A solution of 0.05 g. of cupricacetate monohydrate in 5 ml. of acetic acid is heated to 100° C. and 3.0g. of granular zinc is added. The mixture is shaken for 3 minutes andthe acetic acid is then decanted. The residual zinc-copper couple iswashed three times with 5 ml. portions of acetic acid, then three timeswith 5 ml. portions of ether. It is then refluxed for 4 hours undernitrogen in 20 ml. of ether containing 2.5 ml. of methylene iodide, 1.32g. of 2-hydroxyacetyl-5-oxo-5H-dibenzo[a,d]cycloheptene is added, andreflux is continued for a further 4 hours. The mixture is cooled anddiluted with 50 ml. of benzene. The liquid phase is decanted and washedwith water and aqueous sodium bisulfate, then dried and evaporated. Theresidue is chromatographed on 50 gm. of silica gel, eluting with ethylacetate/hexane, to yield2-(5-oxo-5H-dibenzo[a,d]-cyclohepten-2-yl)prop-1-en-3-ol.

In similar manner substituting2-carboxy-5-oxo-5H-dibenzo[a,d]cycloheptane for the2-carboxy-5-oxo-5H-dibenzo[a,d]cycloheptene, there is prepared2-(5-oxo-5H-dibenzo[a,d]cycloheptan-2-yl)prop-1-en-3-ol.

EXAMPLE III

0.5 G. of 2-(5-oxo-5H-dibenzo[a,d]cyclohepten-2-yl)propan-1-ol isdissolved in 15 ml. of acetonitrile and 2 ml. of acetyl chloride and 1.3ml. of triethylamine are added to the solution. After 1 hour, themixture is poured into water and extracted with ethyl acetate. Theextract is dried and evaporated, then dissolved in ether and passedthrough a silica gel column, and the eluate evaporated to afford2-(5-oxo-5H-dibenzo[a,d]cyclohepten-2-yl)prop-1-yl acetate [an oil, nmrspectrum in deuterochloroform relative to tetramethylsilane, 1.33(doublet, CH₃), 1.98 (singlet, acetoxy), 4.23 (doublet, CH₂) and 7.02ppm (singlet, 10H, 11H); mass spectrum: 306 (M+), 246, 234].

In a similar manner, substituting any of the other alcohols prepared inExamples I and II above for the2-(5-oxo-5H-dibenzo[a,d]cyclohepten-2-yl)propan-1-ol the correspondingacetates are prepared.

Also in similar manner using any of the alcohols prepared in Examples Iand II above and substituting propionyl chloride, butyryl chloride,valeryl chloride, isovaleryl chloride, caproyl chloride, caprylchloride, benzoyl chloride, phenylacetyl chloride, diethylacetylchloride, trimethylacetyl chloride, and cyclopentylpropionyl chloridefor the acetyl chloride, the corresponding esters are prepared,including 2-(5-oxo-5H-dibenzo[a,d]cyclohepten-2-yl)prop-1-yl3'-methylbutyrate (m.p. 79°-80° C.) and 2-(5-oxo-5H-dibenzo[a,d],cyclohepten-2-yl)prop-1-yl dodecanoate (m.p. 40°-41° C.).

EXAMPLE IV

0.45 G. of 2-(5-oxo-5H-dibenzo[a,d]cyclohepten-2-yl)-propan-1-ol isdissolved in 6 ml. of ether, and to the solution is added 0.216 g. ofdihydropyran and 0.001 g. of p-toluenesulphonic acid. After 24 hours, afew drops of triethylamine are added. The solution is then poured intowater and extracted with ethyl acetate. The extract is dried andevaporated and the residue chromatographed on silica gel, eluting withhexane:ethyl acetate (5:1), to afford2-(5-oxo-5H-dibenzo[a,d]cyclohepten-2-yl)prop-1-yl 2'-tetrahydropyranylether [an oil; nmr spectrum in deuterochloroform relative totetramethylsilane: 1.44 (doublet, CH₃), 4.55 (multiplet, O--CH--O) and7.00 ppm (singlet, 10H, 11H); mass spectrum: 348 (M+) 248, 234].

In similar manner, substituting dihydrofuran, and 4-methoxydihydropyranfor the dihydropyran, 2-(5-oxo-5H-dibenzo[a,d]cyclohepten-2-yl)prop-1-yltetrahydrofuran-2-yl ether and2-(5-oxo-5H-dibenzo[a,d]cyclohepten-2-yl)prop-1-yl4'-methoxytetrahydropyran-4'-yl ether are prepared.

Also in similar manner substituting any of the alcohols prepared inExamples I and II above for the2-(5-oxo-5H-dibenzo[a,d]cyclohepten-2-yl)propan-1-ol, the correspondingethers are prepared.

EXAMPLE V

0.48 G. of a 50% mineral oil dispersion of sodium hydride is added to asolution of 2.64 g. of2-(5-oxo-5H-dibenzo[a,d]cyclohepten-2-yl)propan-1-ol in 30 ml. ofdimethylformamide. The mixture is warmed to 40° C. and stirred untilhydrogen evolution ceases. 3.0 G. of ethyl iodide is added and themixture heated to 60° C. for 3 hrs. Water and ether are added and theethereal solution is washed with water, dried and evaporated to yield1-ethoxy-2-(5-oxo-5H-dibenzo[a,d]cyclohepten-2-yl)propane.

In similar manner, substituting methyl iodide, propyl iodide, 2-butyliodide, 3-methylbutyl iodide, chloromethyl methyl ether or chloromethylethyl ether for the ethyl iodide, the corresponding ethers are prepared.Also in similar manner, using any of the alcohols prepared above, thecorresponding ethers are prepared.

EXAMPLE VI

1 G. of 2-acetoxybenzoic acid is added to a solution of 2 ml. oftrifluoroacetic anhydride in 10 ml. of benzene. After 1 hour, thesolution is evaporated and to the residue is added 10 ml. of benzenefollowed by the addition of 1 g. of2-(5-oxo-5H-dibenzo[a,d]cyclohepten-2-yl)propan-1-ol. After 1 hour atroom temperature, the mixture is added to sodium bicarbonate solution.The benzene layer is separated, washed with water and evaporated todryness to afford, upon recrystallization,2-(5-oxo-5H-dibenzo[a,d]cyclohepten-2-yl)prop-1-yl 2'-acetoxybenzoate.

In a similar manner using2-(5-oxo-5H-dibenzo[a,d]cycloheptan-2-yl)propan-1-ol, there is prepared2-(5-oxo-5H-dibenzo[a,d]cycloheptan-2-yl)prop-1-yl 2'-acetoxybenzoate.

Also in similar manner, substituting salicylic acid for the2-acetoxybenzoic acid, the corresponding salicylate esters are prepared.

In similar manner, substituting any of the alcohols prepared above forthe 2-(5-oxo-5H-dibenzo[a,d]cyclohepten-2-yl)propan-1-ol, thecorresponding esters are prepared.

EXAMPLE VII

2.78 G. of 2-(5-oxo-5H-dibenzo[a,d]cyclohepten-2-yl)propionic acid isstirred in a mixture of 20 ml. of benzene and 5 ml. of trifluoroaceticanhydride for 15 minutes. The mixture is evaporated to dryness andredissolved in 20 ml. of dry benzene. A mixture of 1.0 g. of pyridineand 2.44 g. (2 egs.) of (+) α-phenylethanol is added. The mixture isleft for 30 minutes and then water and ether are added. The organiclayer is washed with dilute hydrochloric acid and water, then dried andevaporated. The residue is chromatographed on 100 gm. silica gel,eluting with hexane:ether (4:1) to afford a 1:1 mixture ofdiastereomeric esters. Repeated crystallization of this mixture fromether-hexane yields the less soluble isomer. The purity of samples fromsuccessive recrystallizations is monitored by gas-liquid chromotographyusing a 1 meter × 2 mm. column packed with Chromosorb W (Regis ChemicalCo., Chicago, Ill.) impregnated with 3% w/w OV101 polymeric material(Applied Sciences Laboratory, Inc., State College, Penn.) as stationryphase, and helium as the carrier gas at 220° C. The less soluble isomeris decomposed by stirring in a mixture of 5 ml. of benzene and 5 ml. oftrifluoroacetic acid for 30 minutes. Water and ether are added and theethereal layer washed with water, and then with dilute aqueous sodiumcarbonate. The aqueous layer is acidified with dilute hydrochloric acidand then extracted with ether. The ethereal layer is washed, dried andevaporated to give the resolved(d)-2-(5-oxo-5H-dibenzo[a,d]cyclohepten-2-yl)propionic acid which isrecrystallized from acetone-hexane. The 1-isomer can be obtained insimilar manner using (-) α-phenylethanol.

2.8 G. (0.01) mole of 2-(5-oxo-5H-dibenzo[a,d]cycloheptan-2-yl)propionicacid is dissolved in 25 ml. of isopropanol and 1.35 g. (0.01 mole) ofl-amphetamine is added. The salt crystallizes out and is filtered offand recrystallized several times from isopropanol to constant specificrotation. The salt is suspended in ether and dilute hydrochloride isadded. After shaking, the organic layer is washed, dried and evaporatedto give the resolved(d)-2-(5-oxo-5H-dibenzo[a,d]cycloheptan-2-yl)propionic acid which can berecrystallized from acetone-hexane. The 1-isomer can be obtained insimilar manner using d-amphetamine.

In a similar manner to the procedure of Example I above, substituting(d)-2-(5-oxo-5H-dibenzo[a,d]cyclohepten-2-yl)-propionic acid,(1)-2-(5-oxo-5H-dibenzo[a,d]cyclohepten-2-yl)propionic acid,(d)-2-(5-oxo-5H-dibenzo[a,d]cycloheptan-2-yl)propionic acid, or(1)-2-(5-oxo-5H-dibenzo[a,d]cycloheptan-2-yl)propionic acid for2-(5-oxo-5H-dibenzo[a,d]cyclohepten-2-yl)propionic acid,(1)-2-(5-oxo-5H-dibenzo[a,d]cyclohepten-2-yl)propan-1-ol,(d)-2-(5-oxo-5H-dibenzo[a,d]cyclohepten-2-yl)propan-1-ol [an oil;[α]_(D) + 19.0° (in chloroform, 5 mg./ml.)],(1)-2-(5-oxo-5H-dibenzo[a,d]cycloheptan-2-yl)propan-1-ol,(d)-2-(5-oxo-5H-dibenzo[a,d]cycloheptan-2-yl)propan-1-ol [an oil;[α]_(D) + 14.4° (in chloroform, 5 mg./ml.)] are prepared, respectively.

EXAMPLE VIII

0.45 G. of methyl(5-oxo-5H-dibenzo[a,d]cyclohepten-2-yl)acetate isdissolved in 10 ml. of ether/tetrahydrofuran (1:1) and excess lithiumaluminum hydride is added. After 3 hours, excess hydride is destroyed byaddition of water and the mixture is extracted with ether. The extractis dried and to it is added 2.0 g. of manganese dioxide. The mixture isleft for 4 days and then filtered through celite and evaporated. Theresidue is recrystallized from hexane to afford2-(5-oxo-5H-dibenzo[a,d]cyclohepten-2-yl)ethan-1-ol (m.p. 73°-75° C.).

EXAMPLE IX

The anti-inflammatory activity of the following compounds embracedwithin this invention were compared with the activity of phenylbutazoneby means of the carrageenin-induced rat paw inflammation test describedbelow.

TEST FOR ANTI-INFLAMMATORY ACTIVITY UTILIZING CARRAGEENIN INDUCED PAWINFLAMMATION IN THE RAT

Materials and Methods -- Female rats weighing 80-90 grams are used. Thetest materials are given at hour 0 orally by gavage in 1 ml. aqueousvehicle. At hour 1, 0.05 ml. of a 1% solution (in 0.9% NaCl) ofcarrageenin is injected into the right hind paw. This injection causesan inflammation of the paw. The rats are sacrificed at hour 4, at whichtime both hind paws are removed and weighed separately.

End point: % increase in paw size calculated as follows: ##EQU1##

The results of these tests are summarized in the following table:

    ______________________________________                                                            Oral Anti-Inflammatory                                                        Activity                                                   Compound           (Phenylbutazone = 1)                                      ______________________________________                                        2-(5-oxo5H-dibenzo-                                                            [a,d]cyclohepten-2-yl)-                                                       ethan-1-ol         5                                                         2-(5-oxo-5H-dibenzo                                                            [a,d]cyclohepten-2-yl-                                                        propan-1-ol        6                                                         2-(5-oxo-5H-dibenzo-                                                           [a,d]cyclohepten-2-yl)-                                                       prop-1-yl acetate  ≧3                                                 2-(5-oxo-5H-dibenzo-                                                           [a,d]cyclohepten-2-yl)-                                                       prop-1-yl 3'-methyl-                                                          butyrate           8                                                         2-(5-oxo-5H-dibenzo-                                                           [a,d]cyclohepten-2-yl)-                                                       prop-1-yl dodecanoate                                                                            6                                                         2-(5-oxo-5H-dibenzo-                                                           [a,d]cyclohepten-2-yl)-                                                       prop-1-yl 2'-tetrahydro-                                                      pyranyl ether      6                                                         ______________________________________                                    

2-(5-Oxo-5H-dibenzo[a,d]cyclohepten-2-yl)propan-1-ol was also tested foranalgesic activity in the well-known mouse analgesic (anti-writhing)assay and was found to be at least equipotent, in this assay, withaspirin.

EXAMPLE X

A suspension is prepared having 200 mg. of2-(5-oxo-5H-dibenzo[a,d]cyclohepten-2-yl)propan-1-ol, 0.1% Tween 80(sorbitan monoleate polyoxyethylene; a product of Atlas ChemicalIndustries, Inc.) and 0.5% sodium carboxymethyl cellulose per ml. ofsimple syrup (U.S.P.).

EXAMPLE XI

A solution is prepared having 100 mg. of2-(5-oxo-5H-dibenzo[a,d]cyclohepten-2-yl)propan-1-ol per ml. of solutionof 70% ethanol and 30% simple syrup (U.S.P.).

EXAMPLE XII

    ______________________________________                                        Ingredients        Quantity per tablet, mgs.                                  ______________________________________                                        2-(5-oxo-5H-dibenzo[a,d]-                                                      cyclohepten-2-yl)-propan-1-ol                                                                   300                                                        cornstarch (paste) 30                                                         magnesium stearate 0.5                                                        lactose            100                                                        ______________________________________                                    

The above ingredients are thoroughly mixed and pressed into singlescored tablets.

EXAMPLE XIII

    ______________________________________                                        Ingredients        Quantity per tablet, mgs.                                  ______________________________________                                        2-(5-oxo-5H-dibenzo[a,d]-                                                      cyclohepten-2-yl)propan-1-ol                                                                    250                                                        cornstarch         30                                                         magnesium stearate 0.5                                                        polyvinylpyrrolidone                                                                             25                                                         lactose            to 400                                                     ______________________________________                                    

The above ingredients are thoroughly mixed and pressed into singlescored tablets.

EXAMPLE XIV

    ______________________________________                                        Ingredients       Quantity per capsule, mgs.                                  ______________________________________                                        2-(5-oxo-5H-dibenzo[a,d]-                                                      cyclohepten-2-yl)propan-1-ol                                                                   250                                                         cornstarch         25                                                         lactose           to 350                                                      ______________________________________                                    

The above ingredients are mixed and introduced to a hard-shell gelatincapsule.

EXAMPLE XV

    ______________________________________                                        Ingredients       Quantity per capsule, mgs.                                  ______________________________________                                        2-(5-oxo-5H-dibenzo-                                                           [a,d]cyclohepten-2-yl)-                                                       propan-1-ol      300                                                         lactose           150                                                         magnesium stearate                                                                               8                                                          ______________________________________                                    

The above ingredients are mixed and introduced to a hard-shell gelatincapsule.

EXAMPLE XVI

A suppository totaling 2.8 grams is prepared having the followingcomposition:

    ______________________________________                                        2-(5-oxo-5H-dibenzo[a,d]cyclo-                                                 hepten-2-yl)propan-1-ol                                                                            150 mg.                                                 Witepsol H-15                                                                  (triglycerides of saturated                                                   vegetable fatty acids; a                                                      product of Riches-Nelson,                                                     Inc., New York, N.Y.)                                                                              balance                                                 ______________________________________                                    

EXAMPLE XVII

To a solution of 0.25 g. of 2-(5-oxo-5H-dibenzo[ a,d]-cyclohepten-2-yl)propionyl chloride in 20 ml. of acetonitrile is added 0.20 g. of 2-(5-oxo-5H-dibenzo[ a,d]cyclohepten-2 -yl)propan- 1-ol and 0.40 ml. oftriethylamine. The mixture is left for 16 hours, then evaporated todryness. The residue is dissolved in ethyl acetate and the solution iswashed with water, dilute hydrochloric acid and aqueous sodiumcarbonate, then dried and evaporated. The product is chromatographed onsilica gel, eluting with benzene, to afford 2' -(5-oxo-5H-dibenzo[a,d]cyclohepten-2-yl)prop- 1'-yl 2-(5 -oxo-5H-dibenzo[a,d]cyclohepten-2-yl)propionate [a gum; nmr spectrum indeuterochloroform relative to tetramethylsilane: 1.23 (doublet, CH₃),1.46 (doublet, CH₃), ca. 4.2 (multiplet, CH₂ O) and ca. 6.8 p.p.m.(multiplet, 10H, 11H); Mass spectrum: 524 (m+) 278, 246, 205] .

The propionyl chloride starting material is prepared by dissolving 1.0g. of 2-(5-oxo-5H-dibenzo[ a,d]cyclohepten-2 -yl)propionic acid in 25ml. of chloroform. 1 M1. of thionyl chloride and 0.1 ml. ofdimethylformamide are added thereto and the mixture left for 1 hour,then evaporated to dryness under vacuum to yield the desired product.

In similar manner, substituting 2-(5-oxo-5H-dibenzo[ a,d]-cycloheptan-2-yl)propan-1-ol for the 2-(5-oxo-5H-dibenzo[ a,d]-cyclohepten-2-yl)propan-1-ol, there is obtained 2'-(5-oxo-5H-dibenzo[a,d]cycloheptan-2-yl)prop-1'-yl 2-(5-oxo-5H-dibenzo[a,d]cyclohepten-2-yl)propionate. Also in similar manner, using theappropriate starting materials, 2'-(5-oxo-5H-dibenzo[a,d]cyclohepten-2-yl)prop-1'-yl 2-(5-oxo-5H-dibenzo[a,d]cycloheptan-2-yl)propionate and 2'-(5-oxo-5H-dibenzo[a,d]cycloheptan-2-yl)prop- 1'-yl 2-(5-oxo-5H-dibenzo[a,d]cycloheptan-2-yl)-propionate are prepared.

Also in similar manner using the corresponding optical isomers of theabove alcohols and acids, the respective esters are prepared, including,for example, (1) 2'-(5-oxo-5H-dibenzo-[ a,d]cyclohepten-2-yl)prop-1'-yl(d) 2-(5-oxo-5H-dibenzo[ a,d]-cyclohepten- 2-yl)propioniate.

Separation or purification of the desired product (s) can be byconventional techniques, for example from those described hereinabove.

While the present invention has been described with reference tospecific embodiments thereof, it should be understood by those skilledin this art that various changes may be made and equivalents may besubstituted without departing from the true spirit and scope of theinvention. In addition, many modifications can be made to adapt aparticular situation, material or composition of matter, process,process step or steps, or then-present objective to the spirit of thisinvention without departing from its essential teachings.

What is claimed is:
 1. The pharmaceutically acceptable esters of ahydrocarbon carboxylic acid of from 1 to 12 carbon atoms and a compoundselected from the group of compounds represented by the formula:##STR3## where one of R² and R³ is hydrogen and the other is hydrogen,methyl, or ethyl, or together R² and R³ are methylene; the dotted linerefers to an optional, additional bond between the carbon atoms at the10- and 11-positions.
 2. The compound of claim 1 where both R² and R³are hydrogen.
 3. The compound of claim 1 where there is a single bondbetween the carbon atoms at the 10- and 11-positions.
 4. The compound ofclaim 1 where there is a double bond between the carbon atoms at the 10-and 11-positions.
 5. The compound of claim 1 where said compound is2-(5-oxo-5H-dibenzo[ a,d]cyclohepten-2-yl)ethan-1-ol.
 6. The compound ofclaim 1 where said compound is 2-(5-oxo-5H-dibenzo[a,d]cycloheptan-2-yl)ethan-1-ol.
 7. The pharmaceutically acceptableesters of a hydrocarbon carboxylic acid of from 1 to 12 carbon atoms anda compound selected from the group of compounds represented by theformula: ##STR4## where one of R² and R³ is hydrogen and the other ismethyl.
 8. The compound of claim 7 where there is a single bond betweenthe carbon atoms at the 10- and 11-positions.
 9. The compound of claim 7where there is a double bond between the carbon atoms at the 10- and11-positions.
 10. The compound of claim 7 wherein said compound is2-(5-oxo-5H-dibenzo[ a,d]cyclohepten-2-yl)propan-1-ol.
 11. The compoundof claim 7 wherein said compound is 2-(5-oxo-5H-dibenzo[a,d]cycloheptan-2-yl)propan-1-ol.
 12. The compound of claim 7 whereinsaid compound is d 2-(5-oxo-5H-dibenzo[a,d]cyclohepten-2-yl)propan-1-ol.
 13. The compound of claim 7 whereinsaid compound is d 2-(5-oxo-5H-dibenzo[a,d]cycloheptan-2-yl)propan-1-ol.
 14. The compound of claim 7 whereinsaid compound is 1 2-(5-oxo-5H-dibenzo[a,d]cyclohepten-2-yl)propan-1-ol.
 15. The compound of claim 7 whereinsaid compound is 1 2-(5-oxo-5H-dibenzo[a,d]cycloheptan-2-yl)propan-1-ol.
 16. A compound selected from the groupconsisting of 2-(5-oxo-5H-dibenzo[ a,d]cyclohepten-2-yl)prop-1-ylsalicylate, 2-(5-oxo-5H-dibenzo[ a,d]cycloheptan-2-yl)prop-1-ylsalicylate, 2-(5-oxo-5H-dibenzo[ a,d]cyclohepten-2-yl)prop-1-yl2'-acetoxybenzoate, and 2-(5-oxo-5H-dibenzo[a,d]cycloheptan-2-yl)prop-1-yl 2'-acetoxybenzoate.
 17. The compound ofclaim 1 wherein said compound is selected from the group consisting ofthe acetate, propionate and butyrate esters of the compounds of FormulaI.
 18. The compound of claim 1 wherein said compound is2-(5-oxo-5H-dibenzo[a,d]cyclohepten-2-yl)butan-1-ol.
 19. The compound ofclaim 1 wherein said compound is2-(5-oxo-5H-dibenzo[a,d]cycloheptan-2-yl)butan-1-ol.
 20. The compound ofclaim 1 wherein said compound is2-(5-oxo-5H-dibenzo[a,d]cyclohepten-2-yl)prop-1-en-3-ol.
 21. Thecompound of claim 1 wherein said compound is2-(5-oxo-5H-dibenzo[a,d]cycloheptan-2-yl)prop-1-en-3-ol. 22.2'-(5-oxo-5H-dibenzo[a,d]cyclohepten-2-yl)prop-1'-yl2-(5-oxo-5H-dibenzo[a,d]cyclohepten-2-yl)propionate,2'-(5-oxo-5H-dibenzo[a,d]cycloheptan-2-yl)prop-1'-yl2-(5-oxo-5H-dibenzo[a,d]cyclohepten-2-yl)propionate,2'-(5-oxo-5H-dibenzo[a,d]cyclohepten-2-yl)prop-1'-yl2-(5-oxo-5H-dibenzo-[ a,d]cyclohepten-2-yl)propionate, or2'-(5-oxo-5H-dibenzo-[ a,d]cycloheptan-2-yl)prop-1'-yl2-(5-oxo-5H-dibenzo[ a,d]-cycloheptan-2-yl)propionate.
 23. The compoundof claim 1 wherein said compound is2-(5-oxo-5H-dibenzo[a,d]cyclohepten-2-yl)prop-1-yl acetate.
 24. Thecompound of claim 1 wherein said compound is2-(5-oxo-5H-dibenzo[a,d]cyclohepten-2-yl)prop-1-yl 3'-methylbutyrate.25. The compound of claim 1 wherein said compound is2-(5-oxo-5H-dibenzo[a,d]cyclohepten-2-yl)prop-1-yl dodecanoate.